The regulatory function of the cardiac sarcomere resides in the thin filament. It is a complex macromolecular structure comprised of multiple protein subunits, which interact and modulate contractile function in response to both chronic and acute physiologic stress. The binding of Ca2+ to Troponin C initiates a cascade of allosteric changes in the interactions of the proteins within the troponin (cTnC, cTnl and cTnT) and tropomyosin-actin complexes, facilitating the formation of the actinomyosin complex and the power stroke of muscle contraction. While normal hearts retain the ability to alter these complex interactions, for example, via contractile protein isoform shifts and post-translational modifications, many naturally-occurring thin filament mutations are poorly tolerated. In fact, mutations in cardiac Troponin T (cTnT) result in a particularly severe form of Familial Hypertrophic Cardiomyopathy (FHC) characterized by a high frequency of early sudden cardiac death in the absence of overt ventricular hypertrophy. The direct link between the gene mutation and the complex clinical phenotype remains unknown. Troponin T is a highly elongated protein that interacts with all other components of the thin filament and has been described as the "glue" of the regulatory system. The full ternary structure is unknown and thus the details of these complex protein-protein interactions remain unclear. The hypothesis for this application is that individual cTnT mutations disrupt discrete aspects of these protein-protein interactions causing specific changes in thin filament function and leading to distinct cardiovascular phenotypes. To address this hypothesis we have developed three independent transgenic mouse models based solely on amino acid substitutions at Codon 92 (Arg92GIn, Arg92Trp and Arg92Leu), a known mutational hotspot in human cTnT. Initial characterization has revealed allele-specific changes in cardiac mass, contractility and hypertrophic signaling pathways. In these initial studies we have selected specific aspects of the observed phenotypes to serve as physiologic "indicators" of the differences in thin filament function caused by each mutation. Establishing the mechanistic link between the specific cTnT mutant allele and it's cellular phenotype will both provide new insights into the fundamental biology of thin filament function and further our understanding of the pathogenic pathways involved in thin filament related cardiomyopathies.